AU621318B2

AU621318B2 - Control of ectoparasites

Info

Publication number: AU621318B2
Application number: AU25716/88A
Authority: AU
Inventors: Rudolph Joseph Boisvenue; Gary Dean Crouse
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1987-11-20
Filing date: 1988-11-18
Publication date: 1992-03-12
Anticipated expiration: 2008-11-18
Also published as: CA1299198C; ES2060662T3; ATE109448T1; EP0317275A2; US4870109A; JPH01160937A; JP2610321B2; NZ226968A; DE3850939T2; EP0317275B1; EP0317275A3; AU2571688A; DE3850939D1; ZA888508B

Abstract

A series of 1,3-propanediones having a perfluoroalkyl group or a perfluorocycloalkyl group on one carbonyl, and a 3,5-disubstituted phenyl group on the other, are useful when administered to animals for the control of ectoparasites.

Description

i -i i~ i 621318 S F Ref: 75018 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION i 7;

I

ii

I

(ORIGINAL)

FOR OFFICE USE: Class Int Class

S

It, It, t 5 S S: Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name and Address of Applicant: Address for Service: Eli Lilly and Company Lilly. Corporate Center Indianapolis Indiana 46285 UNITED STATES OF AMERICA Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Control of Ectoparasites The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/5 -2 X-5828B -1- CONTROL OF ECTOPARASITES The present invention relates to novel 1,3propanediones, which have a 3,5-disubstituted phenyl group and a C 2

-C

4 perfluoroalkyl or C 3

-C

6 perfluorocycloalkyl group on the carbonyls, their preparation and use in the control of ectoparasites.

The control of ectoparasites, such as fleas, ticks, biting flies and the like, has long been recogo ao oa: 10 nized as an important problem in animal husbandry. The traditional treatments for domestic animals were topi- .o cally applied insecticides, such as the famous dips for *t sheep. Indeed, such treatments are still in wide use.

However, the more modern thrust of research has been 15 towards compounds which can be administered to the animals, especially orally, and which will control ectoparasite populations by poisoning individual parasites when they ingest the blood of the treated animal. Such a .novel compounds are provided by the present invention.

South African Patent 71/4221 discloses insecticidal activity of 1,3-propanediones having a trifluoro- S"'o methyl group on one carbonyl, and a substituted phenyl group on the other carbonyl. Ectoparasiticidal use of e some of their compounds is disclosed.

25 Canadian Patent 862,068 shows a group of 1,3-propaednediones, having a phenyl or napthyl group on one carbonyl and a perhalomethyl or perhaloethyl group on the other carbonyl. The compounds are said to be insecticides but there is no reference to treatment of animals.

ii 2 U.S. Patent 3,636,214 shows some 1,3-propane-diones having an aryl group on one carbonyl, and a trifluoromethyl or other haloalkyl group on the other carbonyl. However, this document describes the use of such compounds only for the purpose of controlling fungi, especially in the soil.

SUMMARY OF THE INVENTION According to a first embouiment of this invention, there is provided a compound of the formula I I t

*-CO-CH-CO-R

1 10 wherein R, X and Y are as hereinafter defined; or a sodium, potassium or lithium salt thereof.

According to a second embodiment of this invention, there is Sprovided a method of controlling a population of insect or acarina ectoparasites which consume blood of a host animal which comprises administering to the host animal an effective amount of a compound of the first embodiment.

S" According to a third embodiment of this invention, there is provided A, an ectoparasiticidal composition comprising a physiologically-acceptable inert carrier and a compound of the first embodiment.

According to a fourth embodiment of this invention, there is provided a process for preparing a compound of the first embodiment which comprises: A) reacting a compound of formula (I)

(I)

*-CO-CHa with an activated form of the acid of formula (II)

R

1

CO

2 H (II) 2A in the presence of a base sufficiently strong enough to generate the anion of the compound of formula or B) hydrolyzing a compound of the formula -C H-COR 4 OR1

Y

wherein X, Y, R 1 and R are as hereinafter defined.

DESCRIPTION OF THE INVENTION i The present invention provides compounds of the formula

S*X\

S*--CO-CH2-CO-R 1 wherein *1 10 R is a C 2

-C

4 perfluoroalkyl or a C3-C 6 perfluorocycloalkyl; X and Y are each independently chloro, bromo, or fluoro; with the 1 proviso that if R is C 2

F

5 X and Y cannot both be chloro; and the sodium, potassium or lithium salts thereof.

The present invention also provides a method of controlling a population of insect or acarina ectoparasites which consume blood of a host animal which comprises administering to the host animal an effective amount of a compound of the formula *-CO-CH2-CO-R wherein R is C 2

-C

4 perfluoroalkyl or a C 3

-C

6 perfluorocycloalkyl; I 1 4 3 3 6 1 X-5828B -3- X and Y are each independently chloro, bromo, or fluoro; or a sodium, potassium or lithium salt thereof.

Throughout the present document, all temperatures are expressed in degrees Celsius. All expressions of percentage, concentration and the like are in weight units unless otherwise described.

The terms "perfluoroalkyl" and "perfluorocycloalkyl" refer to alkyl or cycloalkyl groups in which S 10 all, or all but one, of the hydrogen atoms have been replaced by fluorine atoms. Thus, the R' groups of the compounds of the present invention include perfluoroalkyl and perfluorocycloalkyl groups such as -CF 2

CF

3

-CF

2

CF

2 H, -CFHCF 3

-CF

2

CF

2

CF

3

-CF

2

CF

2

CF

2 H, -CF 2

CFHCF

3

-CF

2

CF

2

CFCF

3

-CF

2

CF(CF

3 2

-CF

2

CF

2

CFCF

2

H,

-CF

2

CF(CF

2

H)CF

3

-CF

2

CF

2

CFHCF

3

-CF

2 CH(Cv 3 2 1,2,2,3,3pentafluorocyclopropyl, 1,2,2,3-tetrafluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 1,2,2,3,3,4,4-heptafluorocyclobutyl, 1,2,2,3,4,4-hexafluorocyclobutyl, 1,2,2,3,3,4-hexafluorocyclobutyl, 1,2,2,3,3,4,4,5,5nonafluorocyclopentyl, 1,2,2,3,3,4,5,5-octafluorocyclopentyl, 2,2,3,3,4,4,5,5-octafluorocyclopentyl, 1,2,2,3,3,4,4,5,5,6,6-undecafluorocyclohexyl, 1,2,2,3,3,4,4,5,5,6-decafluorocyclohexyl, t 25 1,2,2,3,3,4,5,5,6,6-decafluorocyclohexyl, and the like.

While all of the compounds described above are potent ectoparasiticides, certain compounds are preferred.

Preferred compounds of the present invention are those wherein R' is C 2

-C

4 perfluoroalkyl. Especially preferred compounds of the present invention are those wherein R 1 X-5828B -4is C 2

-C

3 perfluoroalkyl. Even more preferred compounds are those wherein R I is C 2

-C

3 perfluoroalkyl and X and Y are chosen from the group consisting of: X is chloro and Y is chloro; X is bromo and Y is bromo; X is fluoro and Y is fluoro; and sodium, potassium or lithium salts of the above compounds.

The most preferred compounds of the present 10 invention are those compounds wherein R 1 is C 2 -Cs perfluoroalkyl; X and Y are both chloro; and the sodium, potassium, or lithium salts thereof. Particularly preferred compounds, among these most preferred compounds, are 1-(3,5-dichlorophenyl)-3-(l,1,2,2,3,3,3-heptafluoro- S 15 propyl)-l,3-propanedione and 1-(3,5-dichlorophenyl)-3- (1,1,2,2-tetrafluoroethyl)-l,3-propanedione, and the sodium, potassium or lithium salts thereof.

Preferred compounds for use in the method for controlling ectoparasites of this invention are those wherein R 1 is C 2

-C

4 perfluoroalkyl. Especially preferred Scompounds for use in the method of the present invention o are those wherein R I is C 2 -Cs perfluoroalkyl. Even more preferred compounds for use in the presently claimed method are those wherein R 1 is C 2

-C

3 perfluoroalkyl and S 25 X and Y are chosen from the group consisiting of: X is chloro and Y is chloro; X is bromo and Y is bromo; X is fluoro and Y is fluoro; and sodium, potassium or lithium salts of the above compounds.

4 X-5828B The most preferred compounds for use in the method for controlling ectoparasites of this invention are those wherein R 1 is C 2

-C

3 perfluoroalkyl; X and Y are both chloro; and the sodium, potassium or lithium salts thereof. Particularly preferred compounds, among these most preferred compounds, in the method of the present invention are l-(3,5-dichlorophenyl)-3- (1,1,2,2,3,3,3-heptafluoropropyl)-l,3-propanedione, .1 l-(3,5-dichlorophenyl)-3-(l,l,2,2,2-pentafluoroethyl)- 1,3-propanedione, and 1-(3,5-dichlorophenyl)-3-(l,1,2,2i t tetrafluoroethyl)-1,3-propanedione, and the sodium, potassium or lithium salts thereof.

S',Use of any of the above compounds, especially Si' the most preferred compounds enumerated above, in the form of their salts, especially the sodium salt, is particularly preferred in the method for controlling ectoparasites of this invention.

I z While the compounds of the present invention are consistently named as 1,3-propanediones in the present document, it will be understood that it is quite VU possible if not probable that one of the carbonyl groups will actually be in the enol form. That-is to say, the compound will exist in a form described as follows.

1 25 R-CO-CH=C(OH)-R 1 t1 Indeed, it is most probable that the compounds exist in an equilibrium form containing some of the diketone and some of the enol at all times. A careful study of the equilibrium has not been carried out, and X-5828B -6so the compounds will be described here as diketones in all cases. It will be understood by the skilled reader that the principles and function of the present invention remain the same, whether carried out with the diketone, with pure enol, or with an equilibrium mixture of the diketone and the corresponding enol.

It is believed that the nature of the cornpounds used in the present invention has been made entirely clear. However, to assure that the reader fully comprehends the invention, a group of exemplary compounds will be mentioned here.

l-(3,5-dichlorophenyl)-3-(l,l,2,2,2-pentafluoroethyl ,3-propanedione 1-(3,5-dichlorophi nyl)-3-(1,1,2,2-tetrafluoroethyl ,3-propanedione l-(3,5-dichlorophenyl)-3-(l,l,2,2,3,3,3-heptafluoropropyl 3-propanedi one l-(3,5-dichlorophenyl)-3-(1,l,2,3,3,3-hexafluoropropyl ,3-propanedione l-(3,5-dichlorophenyl)-3-(l,1,2,2,3,3,4,4,4nonafluorobutyl ,3-propanedione 1-(3,5-dichlorophenyl)-3-(l,l,2,2,3,4,4,4octafluorobutyl ,3-propanedione 25 l-(3,5-dichlorophenyl)-3-(2-trifluoromethyl- 1,1,3,3, 3-pentafluoropropyl 3-propanedione l-(3 ,5-dichlorophenyl 2,2,3, 3-pentafluorocyclopropyl ,3-propanedione l-(3,5-dichlorophenyl)-3-(1,2,3,3,4,4-hexafluorocyclobutyl ,3-propanedione X- 582 8B -7- 1- 5-difluorophenyl 2-pentafluoroethyl 3-propanedione 1-(3,5-difluorophenyl)-3-(1,1,2,2-tetrafluoroethyl ,3-propanedione 1-(3-5-difluoropheny1)-3-(1,2,2,2-tetrafluoroethyl ,3-propanedione 1-(3,5-difluorophenyl)-3-(1,l,2,2,3,3,3-heptafluoropropyl 3-propanedione 1-(3,5-difluorophenyl)-3-(1,1,2,2,3,3-hexa- 10 fluoropropyl 3-propanedione l-(3,5-difluorophenyl)-3-(l,l,2,2,3,3,4,4,4nonafluorobutyl ,3-propanedione 1- 5-difluorophenyl (2-trifluoromethylo 00 1,1,2,3,3, 3-hexafluoropropyl ,3-propanedione 1-(3,5-difluorophenyl)-3-(1,1,2,2,3,3,4,4octafluorobutyl 3-propanedione 5-iifluorophenyl (2-trifluoromethyl- 1,2,3,3-pentafluoropropyl)-1,3-propanedione a 9 1- 5-difluorophenyl 3-tetrafluorocyclopropyl 3-propanedione l-(3,5-difluorophenyl)-3-(2,2,3,3,4,4-hexa- 04444:flucorocycJlobutyl 3-propanedione 1- 5-dibromophenyl 1,2,2, 2-pentafluoroethyl)-1,3-propanedione *$boo0 25 1-(3,5-dibromophenyl)-3-(l,1,2,2-tetrafluoroethyl) 3-propanedione 1l-(3,5-dibromophenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl 3-propanedione 1-(3,5-dibromophenyl)-3-(l,l,2,2,3,3,4,4,4nonafluorobutyl 3-propanedione X-5828B -8- 21 (3,5 -dibromophenyl) (2 -tri fluoromethyl 1, 1,2,3,3, 3-hexafluoropropyl 3-propanedione '1 1-(3,5-dibromophenyl)-3-(1,2,2,3,4,4-hexafluorocyclobutyl 3-propanedione 1-(3,5-dichlorophenyl)-3-(1,2,2,3,3,4,4,5,5, 6,6undecafluorocyclohexyl 3-propanedione 1-(3 ,5-dibromophenyl)-3-(1,2,2,3,3 6decafluorocyclohexyl 3-propanedione 1 -(3,5-difluorophenyl)-3-(2,2,3,3,4,4,5,5- ~10 octafluiorocyclopent-l yl)-1,3-propanedicne 1-(5-chloro-3-fluorophenyl)-3-(1, 1,2,2,3,3,3heptafluoropropyl) 3-propanedione 1- (3-bromo-5-fluorophenyl (2-trifluoromethyl-1,1,2,3,3,3-hexafluoropropy-l)-1,3-propanedione 1-(5-bromo-3-chlorophenyjj-3-(1,1,2,2,3,3hexe~fluoropropy 3-propanedione 1-(3-bromo-5-fluorophenyl)-3-(1,1,2,2,3,3,4,4,4nonafluorobutyl 3-propanedione T C C1-(3-chloro-5-fluorophenyl)-3-(1,l,2,2-tetrafluoroethyl ,3 -propanedione 4 1- (3-bromo-5-chlorophenyl) (2-trifluoro- ~A methyl-l,l,3,3,3-pentafluoropropyl)-l,3-propanedione 1- (5-bromo-3-chlorophenyl 6-decafluorocyclohexyl)-l,3propanedione According to one aspect of the invention there provided a method for preparing the novel compounds of the invention which have the formula X-5828B -9wherein X, Y and R 1 are as defined above, which comprises reacting a compound of the formula *-CO--CH (I) with an activated form of the acid of formula

R'CO

2 H (II) 1in the presence of a base sufficiently strong enough to S'generate the anion of the compound of formula The activated form of the acid will normally be a Ci-C 4 alkyl ester of the formula R 1

CO

2

R

3 where R 3 is Ci-C 4 alkyl, preferably ethyl. However, acid halides or acid anhydrides can also be used.

As stated above, the reaction should be carried out in the presence of a base strong enough to generate the anion of the compound of formula Suitable bases which may be mentioned are alkali metal ,I hydrides, such as sodium hydride, alkali metal hydroxides, such as sodium methoxide or sodium ethoxide, alkyllithium Scompounds, such as n-butyl lithium, or alkali metal 25 amides such as lithium diisopropyl amide.

The present reaction should be effected at a Stemperature within the range of from about 0 C to about 100 0 C, preferably from about 0 0 C to about room temperature (22 0 in an inert organic solvent such as toluene or diethyl ether.

I

X-5828B When a perfluorocycloalkyl compound is to be made, a preferred synthesis proceeds through a perfluoroalkyl, preferably trifluoromethyl, compound in the alkali metal salt form. That compound is contacted with a strong base, such as sodium hydride, to form an anion, which is then reacted with the acid fluoride of the desired perfluorocycloalkyl carboxylic acid. The reaction is readily carried out at ambient or moderately elevated (up to about 100°C) temperatures.

S. 10 Thus, during the above described reaction, the anion l -CO-CH-COR is generated, wherein R 4 represents C3-C 4 perfluoroalkyl, preferably trifluoromethyl. This anion then reacts with an acid fluoride of the formula RICOF, where R I represents a C 3

-C

6 perfluorocycloalkyl group, to form a compound of the formula

S--CO-H-COR

S2 5 o- o O

R

C

i i X-5828B -11- Hydrolysis of this product with an aqueous mineral acid such as hydrochloric acid yields a compound of the formula 0 0 N ,,-CO-CH2--CO-R 1

S

Y

in which R 1 is C 3

-C

6 perfluorocycloalkyl.

The compounds of the present invention are highly acidic in nature and readily form alkali metal salts. Therefore, the products of the above-described processes are routinely obtained in the salt form. If the free acid form is desired, however, it is only necessary to take the product through an acidic step as the reaction mixture is being worked up. For example, a brief wash with a dilute strong acid, such as dilute hydrochloric acid, readily converts a salt to the free acid.

The following preparative Examples are given to assure that the reader can obtain any desired compound of the present invention. The Examples are not intended to limit the scope of the invention in any respect and should not be so construed.

r X-5828B -12- Example 1 l-(3,5-difluorophenyl)-3-(1,1,2,2,3,3,3-heptafluoropropyl)-1,3-propanedione, sodium salt Sodium ethoxide was prepared by reacting 0.3 g.

of 50% sodium hydride (6.2 mmol. of sodium hydride) and 0.3 g. (6.5 mmol.) of ethanol in 30 ml. of diethyl ether, and to it, at room temperature (220), were added 0.7 g.

(2.9 mmol.) of ethyl 2,2,3,3,4,4,4-heptafluorobutyrate.

S.Then 0.4 g. (2.6 mmol.) of 3,5-difluoroacetophenone were i added dropwise over a period of ten minutes, and the mixture stirred for one hour. The mixture was poured onto ice along with 50 ml. of a 10% disodium hydrogen phosphate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was recrystallized from diethyl ether:hexane to provide 0.78 g. of the desired product. Its n.m.r. spectrum on a 250 mHz instrument showed a singlet at 6 6.30 and broad singlets at 6 7.40 and 7.50, respectively.

Analysis calc. for C 12

H

4

F

9

O

2 Na Theory: C, 38.52; H, 1.08 Found: C, 38.81; H, 1.31 A" 1 y X-5828B -13- Example 2 l-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,-heptafluoropropyl)-1,3-propanedione, sodium salt Sodium ethoxide was prepared by reacting 3.6 g.

of 50% sodium hydride (75.0 mmol. of sodium hydride) and g. (76.0 mmol.) of ethanol in 100 ml. of diethyl ether.

The solution was cooled to about 50 and 9.0 g. (37.0 mmol.) of ethyl 2,2,3,3,4,4,4-heptafluorobutyrate were {added. Then 7.0 g. (37.0 mmol.) of phenone were added and the mixture stirred for two hours.

The mixture was poured onto ice along with 50 ml. of a 10% disodium hydrogen phosphate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was recrystallized from diethyl ether:hexane to provide approximately 10 g. of the desired product. Its n.m.r.

S" spectrum on a 250 mHz instrument showed singlets at S, 20 6 6.35, 7.75, and 7.85, respectively.

Analysis calc. for C 12

H

4 Cl 2 F7O 2 Na Theory: C, 35.41; H, 0.99 Found: C, 35.68; H, 1.26 'C In an analogous manner to that described in Example 2, the following compounds were prepared: X-582 a *t t 4 a 20 t I I 8B 1 -14- Example 3 l-(3,5-Dichlorophenyl)-3-(1,1,2,2,2-pentafluoroethyl)-1,3-propanedione, sodium salt.

Ethyl 2,2,3,3,3-pentafluoropropionate (30.0 g., 156.0 mmol.) and 3,5-dichloroacetophenone (23.2 g., 123.0 mmol.) were reacted to provide the title compound.

The compound's n.m.r. spectrum on a 250 mHz instrument showed a singlet at 6 6.35 and a broad singlet at 6 7.8-7.9.

Analysis calc. for C 11

H

4 C1 2 F50 2 Na Theory: C, 37.00; H, 1.13 Found: C, 36.93; H, 1.40 Example 4 l-(3,5-Dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3-propanedione, sodium salt 2,2,3,3-Tetrafluoropropionyl chloride (5.5 g., 33.0 mmol.) and 3,5-dichloroacetophenone (5.6 29.6 mmol.) were reacted to provide the title compound, which was then recrystallized from hexane to provide an offwhite solid. The compound's n.m.r. spectrum on a 250 mHz instrument showed a singlet at 6 6.30 a triplet of triplets at 6 6.65 a singlet at 6 7.80 and a singlet at 6 7.85 (2H).

X-5828B Mass spectrum analysis established that this compound exists as a dimer and a trimer, containing from one to three sodium cations.

Analysis calc. for a trimer of the formula

C

33

H

16 Cl 6 F2gO 6 Na 2 Theory: C, 39.83; H, 1.62 Found: C, 39.81; H, 1.92 Example l1-(3,5-Dibromophenyl)-3-(1,1,2,2,3,3,3-hepta- S fluoropropyl)-1,3-propanedione, sodium salt 15 Ethyl 2,2,3,3,4,4,4-heptafluorobutyrate (4.0 g., S.16-.5 mmol.) and 3,5-dibromoacetophenone (4.2 15.0 mmol were reacted to provide 5.0 g. of the title compound as a light yellow powder. The product compound had a melting point of 131-1340. Its n.m.r. spectrum on 20 a 250 mHz instrument showed a singlet at 6 6.30 (1H) and a broad singlet at 6 8.00 (3H).

s r SMass spectrum analysis established that this compound exists as a dimer, containing one or two sodium it 25 cations.

l t Analysis calc. for a dimer of the formula

C

2 4

H

9

F

1 4 Br 4 0 4 Na Theory: C, 29.75; H, 0.93 Found: C, 29.78; H, 1.05 SMM/650Z X-5828B -16- Representative compounds of the present invention have been tested both in vitro and in vivo to determine the scope of their activity. The following tests are illustrative.

Single Dose Cattle Systemic Test Representative compounds were tested in cattle using a single intraruminal injection of the desired dose of the compound dissolved in 10 ml. of polyethylene glycol. The cattle were calves weighing at least 165 kg., I housed in environmentally controlled pens. Two calves E were used for each compound tested. The calves were fed on a conventional mixed feed which provided adequate nutrients and energy. Feed and water were available to the calves at all times.

Each day, a sample of blood was obtained from the jugular vein of each calf. The blood samples were centrifuged to obtain serum, and the serum was exposed to insects as described below. Thus, the tests evaluated the systemic activity of the compounds, and also the length of time during which the compound persisted in the animal's system.

In one in vitro method used to evaluate compound activity, dental wicks were saturated with the above blood serum and then placed in Petri dishes containing adult stable flies and in test tubes containing blow fly larvae. After 24 hours, the insects were examined and the number of dead counted. A compound was considered to be active, for purposes of the present I I i- i X-5828B -17disclosure, on any day in which at least 50% of the insects were killed upon exposure to the saturated wick.

Certain compounds were further tested by exposing dental wicks saturated with blood serum, per the method described above, to insects for 48 hours rather than 24 hours. After 48 hours, the insects were examined and the number of dead counted. Again, a compound was considered to be active, for purposes of the present disclosure, on any day in which at least 50% of the insects were killed upon exposure to the saturated wick.

:The following table reports test results of representative compounds of the present invention. The compounds are identified by their Example numbers above.

Insecticidal results are reported in terms of "days of 4' <insecticidal activity", indicating the specific test days on which at least 50% of the insects were killed upon exposure to a serum saturated dental wick for either a 24 or 48 hour period.

I

*a r ii X-5828B -18- Table I Insecticidal Activity Following 24 and 48 Hour In Vitro Exposure of Insects to Cattle Sera Days of Insecticidal Activity 24 Hours 48 Hours 4t 1911 t 1 15 Compound of Ex.

Number 2 2 3 3 4 4 Dose (mg./kg.) 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Test Days 10 10 10 10 10 10 10 10

L

2-4 2-3 0* 0* 0 0 0* 0*

A

2-4 2-4 2-3 0 0 0 2-3 3

L

1-6 1-6 3-4+ 3-4 0 0

NT

A

1-8, 1-10 3-6 0 0+

NT

Ii L Blow Fly Larvae A Adult Stable Fly NT Not Tested Blow Fly Larvae alive but stunted in size (Compound of Example 4 days 3 and 4, Compound of Example 6 days 4 and Not tested on days 1, 2 or 7-10.

Multiple Dose Cattle Systemic Test Representative compounds of the invention were also tested in cattle using multiple intraruminal injections of the desired dose of the compound. The multiple injections consisted of daily administration of a single intraruminal injection for a period ranging from 10 to X-5828B -19- 18 days. The cattle tested were similar in size to those described for the single dose test detailed above.

Two calves were used for each compound and dose tested.

The calves were also fed and watered as previously described.

The daily dose of compound to be tested was prepared using one of two methods. In one method the desired dose was prepared, daily, prior to administration, by dissolving the required daily amount of test compound in 5 ml. of polyethylene glycol. In an alternative I irmethod the entire amount of compound required for the test was dissolved in a sufficient amount of polyethylene glycol such that the resulting solution contained approximately 5 ml; of polyethylene glycol for each day of testing. The total volume of material thus prepared t fwas then placed in a capped serum bottle which was suitable for metering out the desired daily dose.

Approximately 24 hours after the previous day's intraruminal dose had been administered, and just before the current day's dose was to be administered, a sample of blood was obtained from the jugular vein of each calf tested. The blood samples were centrifuged to obtain serum and the serum exposed to adult stable flies and blow fly larvae per the 24 and 48 hour in S25 vitro test system described previously.

It'i In addition, certain representative compounds of the present invention were also tested using an in vivo test system comprising placing a chamber containing six starved adult stable flies on the back of the test animal on each test day. The flies were collected daily 1 X-5828B and the number of dead flies counted. A compound was considered to be active, for purposes of the present discussion, on any day in which at least 50% of the flies had died prior to collection.

The calves were given daily intraruminal injections for periods ranging from 10 to 18 days and then the injections were stopped. Both in vitro and in vivo li testing was continued for several days beyond the administration period, preferably until no further insecticidal activity was observed. Thus, the tests V evaluated the systemic activity of the compounds, and also the length of time during which the compound persisted in the animal's syste, Tables II and III report test results of reprei 15 sentative compounds. The compounds are identified by J t their Example numbers above. Table II reports insecticidal activity in the 24 and 48 hour in vitro test system.

Table III reports insecticidal activity against adult stable flies in the in vivo test system. Insecticidal S 20 results, in both tables, are reported in terms of "days c, of insecticidal activity". The term "days of insecticidal activity" in Table II is used in the same manner as in Table I above. The same term, in Table III, refers to the specific test days in which at least t 25 of the adult stable flies had died prior to collection.

-le I- 1 0 Table II I Insecticidal Activity Following 24 and 48 Hour In Vi*wo Exposure of Insects to Cattle Sera Compound of Daily Dose Example No. (mg/kg/day) 1.00 1.00 0.50 0.50 0.35 0.35 0.20 0.20 1.50 1.50 1.00 1.00 0.75 Dose Time (Days) 18 18 17 17 17 17 17 17 10 10 18 18 10 Days of Insecticidal Activity Test 24 Hours 48 Hours Days L A L A 26 21* 25 25 25 25 25 25 19 19 26 26 19 6-26 5-21 0 0 0 0 0 0 4-18 4-16 5-23 5-22 6-11 3-26 3-21 10-11 12 0 0 0 0 2, 4-19 3-19 3-25 3-25 5, 8-14

NT

7-16, 18-19 8-15 0 0 0 0 2-19 2-18

NT

4-13

NT

4, 6-21 4, 6-19 7, 9-18 6, 8-18 0 0 2-19 2-19

NT

3-17 0 0 06 0 0 0 0 00 0~ 000 0 0 00 00 0 000 000 a 0 0 0 00 a. ft a a 0 Oe 0 *00 0 4 0*0 Table II cont'd.

Compound of Example No.

Daily Dose (mg/Kg/day) Dose Time Test 24 Hours Days L A 48 Hours L A 0.75 0.50 0.50 0.30 0.30 1.00 1.00 7-10 0 0 0 0 9-11 10-11 10-12 0 0 4-13 6-12 6-12 0 0 4-17 4,6-18 4,6-16,18 4,9,12 4, 8, 10-11,16 3-18 5-18 4,6-9,11,17 6,8,9,11,17 L Blow Fly Larvae A Adult Stable Fly NT Not Tested Test animal died on day 21 r* X-5828B -23- Table III In Vivo Insecticidal Activity Compound Dose Days of of Ex. Dose Time Test Insecticidal Number (mg./kg./day) (Days) Days Activity 2 1.00 18 26 4-13,15-22, 25-26 2 1.00 18 21* 1,6-12,15-21 3 1.00 18 260 4-8,10-13, 15-26 i 3 1.00 18 26- 5-13,15-26 +Data not available for day 14.

*Test animal died on day 21; Data not avail able for days 2-5 and 13-14.

OData not available for days 9 and 14.

Tick Test 4, The activity of the compounds of the invention against Lone Star ticks, Amblyomma americanum, was deter-

S

r 1 mined as follows. Two calves were given a daily 1 mg./kg.

1 it intraruminal injection of a solution consisting of the required amount of the compound of Example 2 dissolved in 5 ml. of polyethylene glycol. Two other calves were S. given a daily 1 mg./kg. intraruminal injection of a solution consisting of the required amount of the compound of Example 3 dissolved in 5 ml. of polyethylene glycol. Finally, two other calves were used as control calves, with one calf given 5 ml. of polyethylene glycol X-5828B -24each day while the other calf was left untreated. All treatments continued for a total of 18 days.

Forty (20 female and 20 male) adult Lone Star ticks were placed on each calf seven days after the treatments described above were started. In addition, Lone Star tick nymphs were placed on each test animal at this same point in time. Eleven days later the calves were examined to assess the compounds' efficacy on adult and nymph tick viability. The results of this 10 test are presented in Table IV below.

Table IV Compound Efficacy Against Adult and Nymph Ticks

I

i i

I;

1 i 4 I4 4+ z 1(1 111: Calf Treatment 1 mg./kg./day of Compound of Example 2 in 5 ml.

of polyethylene glycol 1 mg./kg./day of Compound of Example 3 in 5 ml.

25 of polyethylene glycol ml./day of polyethylene glycol 30 No treatment Tick Viability After 11 Days Exposure All nymphs dead; No adult ticks repleted; All female adult ticks dead.

All nymphs dead; No adult ticks repleted; All female adult ticks dead.

16/30 nymphs alive; All adult ticks repleted; All female adult ticks alive and normal in egg production.

18/30 nymphs alive; All adult ticks repleted; All female adult ticks alive and normal in egg production.

c I I, :ii ICI X-5828B Methods of Use The method of the present invention is carried out by administering a compound of the invention to a host animal to control insect and acarina parasites.

Administration to the animal may be by the oral or percutaneous routes.

Parasitic insects and acarina include species that are bloodsucking as well as flesh eating and are parasitic during all of their life cycle or only part of their life cycle, such as only the larval or only the .ift" adult stage. Representative species include the following: horse fly Tabanus spp.

stable fly Stomoxys calcitrans black fly Simulium spp.

horse sucking louse Haematopinus asini mange mite Sarcoptes scabiei scab mite Psoroptes equi S 20 horn fly Haematobia irritans cattle biting louse Bovicola bovis shortnosed cattle louse Haematopinus eurysternus longnosed cattle louse Linognathus vituli t t 1 25 tsetse fly Glossina spp.

cattle follicle mite Demodex bovis cattle tick Boophilus microplus and B. decoloratus Gulf Coast tick Amblyomma maculatum Lone Star tick Amblyomma americanum X-5828B -6 -26-

A

ear tick Rocky Mountain wood tick screwworm fly assassin bug mosquito brown ear tick African red tick bont tick bont legged tick hog louse chigoe body louse foot louse sheep ked sheep scab mite greenbottle fly black blow fly secondary screw-worm sheep blow fly bed bug Southern chicken flea fowl tick chicken mite scalyleg mite depluxning mite dog follicle mite dog flea American dog tick brown dog tick Otobius megnini Dermacentor andersoni Cochliomyia hominivorax Reduvius spp.

Culiseta inornata Rhip icephalus appendi cul atus Rhipicephalus; evertsi Alnblyomma sp.

Hyalonuna sp.

Haematopinus suis Tunga penetrans Haematopinus ovillus Linognathus pedalis Melophagus ovinus Psoroptes ovis Phaenicia sericata Phormia regina Cochliomyia macellaria Phaenicia cuprina Cimex lectularius Echidnophaga gallinacea Argas persicus Dermanyssus gallinae Knemidokpte mutans Kuiemidokoptes gallinae Demodex canis Ctenocephalis canis Dermacentor variabilis Rhipicephalus sanguineus X-5828B -27- The method of the invent on may be used to protect economic and companion animals from ectoparasites. For example, the compounds may beneficially be administered to horses, cattle, sheep, pigs, goats, dogs. cats and the like, as well as to exotic animals such as camels, llamas, deer and other species which are commonly referred to as wild animals. The compounds may also beneficially be administered to poultry and other I birds, such as turkeys, chickens, ducks and the like.

i 1. I0 Preferably, the method is applied to economic animals, and most preferably to cattle and sheep.

The claimed compounds display systemic ectot .parasiticidal activity. The compounds have the ability Sto permeate the tissues of a host animal to which one of the compounds has been administered. Insect parasites which then consume blood or other living tissues of the I ,host animal are thereby killed. Hence, the term "controlling", as defined for purposes of the present disclosure, entails the destruction of an insect population by killing the undesired insects after thay have consumed blood or other living tissue from the host animal. The compounds can be administered by oral or percutaneous routes, and are preferably formulated prior to administration.

Percutaneous administration is conveniently I accomplished by intraperitoneal, intraruminal and intravenous injection of an injectable formulation.

Oral administration is a particularly preferred route of administration. The rate, timing, and manner of effective administration will vary widely with the identity of the parasite, the degree of parasiticidal attack, and other factors. Administration can be made periodically over the entire lifespan of the host, or X-5828B -28for only a peak season of parasitic attack. In general, effective parasite control is achieved at administration rates of from about 5 to about 100 mg./kg. Oral administration may be performed by mixing the compound in the animals' feed or drinking water, or by administering dosage forms such as tablets, capsules, boluses, or implants.

Since ectoparasitic attack generally takes place during a substantial portion of the host animal's Slifespan, it is preferred to orally administer the com- I0 pounds of the present invention in a dosage form capable of providing sustained release over a period of time.

O, Conventional procedures include the use of a matrix e~* which physically inhibits dissolution, where the matrix is a waxy semisolid, such as a vegetable wax, a high e molecular weight polyethylene glycol, or a copolymeric matrix such as that described in Nevin, U.S. Patent o'o 4,273,920. A good way to administer the compounds is S9 t .by means of a sustained-action bolus, such as those of Laby, U.S. Patent 4,251,506, Davis et al., U.S. Patent 4,649,042 and Simpson, British Patent 2,059,767. Susr tained release of the compounds of the present invention can also be achieved by the use of an implant such as from a silicone-containing rubber.

*.9 Usually, the compounds are formulated into ectoparasiticidal compositions which comprise a compound of the present invention and a physiologically-acceptable carrier. Such formulations are well known to those skilled in the art, for example by dissolving or dispersing the compound in one of many physiologicallyacceptable adjuvants or diluents.

The compounds can be formulated for oral administration in the usual forms, such as drenches, tablets, or capsules. Such compositions, of course, require orally-acceptable inert carriers. The compounds can iI X-5828B -29also be formulated.as an injectable soluticn or suspension, for intraperitoneal, intraruminal or intravenous injection.

In some applications, the compounds are conveniently formulated as one component of a standard animal feed. In this embodiment, it is usual to formulate the compound first as a premix in which the compound is dispersed in a liquid or particulate solid carrier. The premix can contain from about 2 to 250 grams of compound per pound. The premix is then, in turn, formulated into the ultimate feed by conventional mixing.

The following exemplary compositions illustrate the sort of formulations used to practice the present invention.

Feed Premix Compound of Example 2 Rice hulls Light mineral oil Feed Premix J Compound of Example 3 Alfalfa meal Powdered clay Molasses Suspension Compound of Example 1 Naphthalenesulfonate salt Nonionic surfactant Fumed silica 1 Water 59 X-5828B Drip-On Solution Compound of Example 4 Nonionic surfactant 0.8 Propylene glycol Water 64.2 Drip-On Suspension Compound of Example 5 Nonionic surfactant 1 10 Light mineral oil 89 Injectable Solution Compound of Example 3 Propylene glycol Injectable Solution Compound of Example 2 Polyethylene glycol Injectable Suspension Compound of Example 3 Propylene glycol Water Injectable Suspension Compound of Example 4 Polyvinylpyrrolidone 2 Water 68

Claims

1. A compound of the formula 6 *--CO--CH2--CO--R wherein R 1 is a C 2 -C 4 perfluoroalkyl or a C 3 -C 6 perfluorocycloalkyl; X and Y are each independently chloro, bromo, ju or fluoro; with the proviso that if R 1 is C 2 F 5 X and Y t cannot both be chloro; or a sodium, potassium or lithium salt thereof.

2. A compound of Claim 1 wherein R 1 is C 2 -C 3 perfluoroalkyl or a sodium, potassium or lithium salt thereof. 'to

3. A compound of Claim 2 wherein X and Y are 44 the same and are chloro, bromo, or fluoro; or a sodium, 20 potassium or lithium salt thereof. I

4. A compound of-Claim 3, said compound being l-(3,5-dichlorophenyl)-3-(1,1,2,2,3,3,3-heptafluoro- propyl)-1,3-propanedione; or a sodium, potassium or lithium salt thereof.

5. A compound of Claim 3, said compound being l-(3,5-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,3- propanedione; or a sodium, potassium or lithium salt thereof.

6. A method of controlling a population of insect or acarina ectoparasites which consume blood of X-5828B-(EPO) -32- a host animal which comprises administering to the host animal an effective amount of a compound of the formula 6O 0 *--CO.-CH2--CO--R wherein RI is a C 2 -C 4 perfluoroalkyl or a C 3 -C 6 perfluorocycloalkyl; cc~. X and Y are each independently chloro, bromo, S or fluoro; or C *0 a sodium, potassium or lithium salt thereof.

7. A m~thod of Claim 6, wherein the compound used is l-(3,5-dichlorophenyl)-3-(l,l,2,2,3,3,3-hepta- fluoropropyl)-l,3-propanedione or a sodium, potassium, or lithium salt thereof. t 0

000008. A method of Claim 6 wherein the com- 0pound is l-(3,5-dichlorophenyl)-3-(l,l,2,2,2-penta- :20 fluoroethyl)-l,3-propanedione or a sodium, potassium, 0 or lithium salt thereof. O 0

9. A method of Claim 6 wherein the com- pound is l-(3,5-dichlorophenyl)-3-(l,l,2,2-tetrafluoro- .04 O: ethyl)-l,3-propanedione or a sodium, potassium, or 0025 lithium salt thereof.

An ectoparasiticidal composition compris- ing a physiologically-acceptable inert carrier and a compound of the formula IS 0~ *--CO--CH2-O-R 1 Yr/ 0S( X-5828B-(EPO) -33- wherein R 1 X and Y are as defined in Claim 6.

11. A process for preparing a compound of the formula X\ s 0-* o-CO-CH--CO-R Y/ wherein R 1 X, and Y are as defined in Claim 1, which S 10 comprises: t c t A) reacting a compound of formula (I) o-CO-CHa (I) with an activated form of the acid of formula (II) R 1 CO 2 H (II) in the presence of a base sufficiently strong enough to J 20 generate the anion of the compound of formula or t B) hydrolyzing a compound of the formula n, S*-O-C H-COR y/ wherein X and Y are as defined in Claim 1, R' is C 3 -C 6 perfluorocycloalkyl and R 4 is C 1 -C 4 perfluoroalkyl. 34

12. A compound of the formula *-CO-CHa-CO-R or a sodium, potassium or lithium salt thereof, wherein R 1 X and Y are as defined in Claim 1, which compound is substantially as hereinbefore described with reference to any one of Examples 1 to

13. A process for preparing 1,3-propanedione derivatives as defined in Claim 1, which process is substantially as hereinbefore described with reference to any one of Examples 1 to

14. A veterinary composition for the control of an ectoparasitic infestation of an animal, which composition comprises an amount effective as an ectoparasiticide for said animal of a compound as defined in Claim 12 together with a veterinarily acceptable carrier, diluent, adjuvant and/or excipient.

The composition of Claim 14 wherein said ectoparasitic infestation is insect or acaridic.

16. A method of controlling an ectoparasitic infestation of an animal which method comprises administering to an animal in need of ectoparasite control, an amount effective as an ectoparasiticide for said animal of a compound as defined in Claim 12, or a composition as defined in Claim 14.

17. The method of Claim 16 wherein said ectoparasitic infestation is insect or acaridic. DATED this TWENTY-FOURTH day of OCTOBER 1991 Eli Lilly and Company Patent Attorneys for the Applicant SPRUSON FERGUSON LMM/650Z